Process for preparing 4,5-dihydro-4-oxofuran-2-carboxylic acid derivatives

ABSTRACT

Derivatives of 4,5-dihydro-4-oxofuran-2-carboxylic acid characterized by having two substituents at position 5 and in addition being optionally further substituted at position 3 with a lower alkyl group, as well as esters therefor are disclosed. The foregoing compounds are useful hypolipidemic agents in a mammal. Novel methods for the preparation of these compounds also are disclosed.

BACKGROUND OF THE INVENTION

a) Field of the Invention

This invention relates to novel derivatives of4,5-dihydro-4-oxofuran-2-carboxylic acid, to therapeutically acceptablesalts thereof, to processes for their preparation, to methods for usingthe derivatives and to pharmaceutical compositions of the derivatives.

More specifically, the present invention relates to novel derivatives of4,5-dihydro-4-oxofuran-2-carboxylic acid having two substituents atposition 5 and in addition being optionally further substituted atposition 3 with a lower alkyl group as well as esters thereof. Thesederivatives are useful as hypolipidemic agents in a mammal at dosageswhich do not elicit undesirable side effects.

B) Description of the Prior Art

4,5-Dihydro-4-oxofuran derivatives are extensively described in theliterature. Additionally, derivatives of4,5-dihydro-4-oxofurancarboxylic acids have also been disclosed. Forexample, 4,5-dihydro-2-methyl-4-oxofuran-3-carboxylic acid and its ethylester are described by R. E. Rosenkranz et al., Helv. Chim. Acta., 46,1259 (1963) and references cited therein. In addition, this referencediscloses the structure of 4,5-dihydro-5-methyl-4-oxofuran-2-carboxyicacid as a hypothetical intermediate during the decarboxylation of4-methoxy-5-methylfuran-2-carboxylic acid. The presence of4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid was not confirmed byisolation or other means.

Recently a few furan derivatives were reported to be hypolipidemicagents. More specifically, some derivatives of2,3,4,5-tetrahydro-3-oxo-4-hydroxy-iminofurans, 2,5-dihydrofurans and2,3,4,5-tetrahydrofurans are described to have weak to moderatehypolipidemic activity by G. B. Bennett et al., J. Med. Chem., 19,709(1976). However, the latter report also states that the furanderivatives, disclosed therein, are devoid of a desirable level ofhypolipidemic activity.

The 4,5-dihydro-4-oxofuran-2-carboxylic acid derivatives of thisinvention are novel compounds having hypolipidemic activity withoutaffecting liver weight.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula I ##STR1## inwhich R¹ and R² each is lower alkyl, cyclo(lower)alkyl, lower alkoxy(lower)alkylene, phenyl or phenyl mono- or disubstituted with loweralkyl, lower alkoxy, halo, nitro or trifluoromethyl; or R¹ and R²together form a --(CH₂)_(m) --X--(CH₂)_(n) --chain wherein m and n eachis an integer from one to four and X is methylene, oxa or thia; or R¹and R² together with the carbon atom to which they are joined form aspiro-[1,2,3,4-tetrahydronaphthalene]-1or spiro[indan]-1-radical; R³ ishydrogen or lower alkyl; and R⁴ is hydrogen, lower alkyl,cyclo(lower)alkyl, phenyl-(lower)alkylene, amino(lower)alkylene, loweralkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene, or a therapeutically acceptable additionsalt thereof.

A preferred group of compounds of formua I are those in which R¹ islower alkyl, phenyl or phenyl monosubstituted with halo; R² is loweralkyl; or R¹ and R² together with the carbon atom to which they arejoined form a spiro[1,2,3,4-tetrahydronaphthalene]-1 radical; R³ ishydrogen; and R⁴ is hydrogen, lower alkyl or 3-pyridinyl(lower)alkylene,or a therapeutically acceptable addition salt thereof.

A most preferred group of compounds of formula I are those in which R¹is lower alkyl, phenyl or 4-chlorophenyl; R² is lower alkyl; or R¹ andR² together with the carbon atoms to which they are joined form a spiro[1,2,3,4-tetrahydronaphthalene]-1 radical; R³ is hydrogen; and R⁴ ishydrogen, lower alkyl or 3-pyridinyl methyl, or a therapeuticallyacceptable addition salt thereof.

The compounds of formula I in which R¹, R², R³ and R⁴ are as definedherein are prepared by a process, which comprises:

cyclizing a compound of formula X ##STR2## in which R¹, R² and R³ are asdefined herein under acidic conditions to obtain the correspondingcompound of formula I in which R¹, R², and R³ are as defined herein andR⁴ is hydrogen, and if desired, esterifying the latter compound offormula I to obtain the corresponding compound of formula I in which R¹,R² and R³ are as defined herein and R⁴ is lower alkyl,cyclo(lower)alkyl, phenyl(lower)alkylene, amino(lower)alkylene, loweralkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene.

More specifically, the compounds of formula I in which R¹, R², R³ and R⁴are as defined herein are prepared by a process, which comprises:

reacting a compound of formula II ##STR3## in which R¹, R² and R³ are asdefined herein with a di(lower alkyl)oxalate in the presence of a stronginorganic proton acceptor under anhydrous conditions, hydrolyzing themixture with water at pH 10 to 12, and allowing the latter mixture tostand under acidic conditions to obtain the corresponding compound offormula I in which R¹, R² and R³ are as defined herein and R⁴ ishydrogen; and if desired

esterifying the latter compound of formula I to obtain the correspondingcompound of formula I in which R¹ , R² and R³ are as defined herein andR⁴ is lower alkyl cyclo(lower)alkyl,phenyl(lower)alkylene,amino(lower)alkylene, lower alkylamino(lower)alkylene, di(loweralkyl)amino-(lower)alkylene, or 3-pyridinyl(lower)alkylene.

The compounds of formula I, or a therapeutically acceptable additionsalt thereof, lower lipid levels in a mammal when administered to saidmammal in an effective hypolipidemic amount.

A convenient form for administering the compounds involves apharmaceutical composition comprising a compound of formula I or atherapeutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein means straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radicals containing three or four carbon atoms and includesmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyland the like.

The term "lower alkoxy" as used herein means straight chain alkoxyradicals containing from one to six carbon atoms and branched chainalkoxy radicals containing three or four carbon atoms and include amethoxy, ethoxy, isopropoxy, n-butoxy, n-hexyloxy and the like.

The term "lower alkylene" as used herein means a divalent organicradical derived from either straight and branched chain aliphatichydrocarbons containing from one to six carbon atoms by removal of twohydrogen atoms and includes methylene, ethylene, 1-methylpropylene,2-methylpropylene, 2-ethylpropylene, 2-butylethylene and the like.

The term "cyclo(lower)alkyl" as used herein means saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower alkanol" as used herein means both straight and branchedchain alkanols containing from one to four carbon atoms and includesmethanol, ethanol, isopropanol, butanol and the like. The term "stronginorganic proton acceptor" as used herein means the inorganic bases,preferably the alkali metals, the alkali metal hydrides, amides,hydroxides and alkoxides, for example, sodium, sodium hydroxide,potassium hydroxide, sodium ethoxide, sodium methoxide, sodium hydrideand the like.

The term "lower alkanoyl" as used herein means straight chain alkanoylradicals containing from two to six carbon atoms and a branched chainalkanoyl radical containing four carbon atoms and includes acetyl,propionyl, isobutyryl, n-hexanoyl and the like.

The term "organic proton acceptor" as used herein means the organicbases, or amines for instance, triethylamine, pyridine,N-ethylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene and the like.

The term "therapeutically acceptable addition salt" as used hereinincludes the therapeutically acceptable acid addition salts of thecompound of formula I in which R⁴ is amino(lower)alkylene, loweralkylamino(lower)-alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene. The acid addition salts are prepared byreacting the base form of the appropriate compound of formula 1 with oneor more equivalents, preferably with an excess, of the appropriate acidin an organic solvent, for example, diethyl ether or an ethanol-diethylether mixture. These salts, when administered to a mammal, possess thesame pharmacologic activities as the corresponding bases. For manypurposes it is preferable to administer the salts rather than the basecompounds. Suitable acids to form these salts include the common mineralacids, for instance hydrohalic, sulfuric or phosphoric acid; as well asthe organic acids, for instance, formic, acetic, maleic, malic,ascorbic, succinic, fumaric, citric, or tartaric acid; or acids whichare sparingly soluble in body fluids and which impart slow-releaseproperties to their respective salts such as pamoic or tannic acid orcarboxymethyl cellulose. The addition salts thus obtained are thefunctional equivalent of the parent base compound in respect to theirtherapeutic use. Hence. these addition salts are included within thescope of this invention and are limited only by the requirement that theacids employed in forming the salts be therapeutically acceptable.

Furthermore, the term "therapeutically acceptable addition salt" as usedherein also includes the therapeutically inorganic or organic baseaddition salts of the compound of formula 1 in which R⁴ is hydrogen,i.e. compound of formula 1 which are acids. These derived salts possessthe same activity as the parent acid and are included within the scopeof this invention. The acid is transformed in excellent yield into thecorresponding therapeutically acceptable salt by neutralization of saidacid with the appropriate inorganic or organic base. The salts areadministered in the same manner as the parent acid compounds. Suitableinorganic bases to form these salts include, for example, thehydroxides, carbonates, bicarbonates or alkoxides of the alkali metalsor alkaline earth metals, for example, sodium, potassium, magnesium,calcium and the like. Suitable organic bases include the followingamines; lower mono-di- and trialkylamines, the alkyl radicals of whichcontain up to three carbon atoms, such as methylamine, dimethylamine,trimethylamine, ethylamine, di- and triethylamine,N-methyl-N-ethylamine, and the like; mono-, di and trialkanolamines, thealkanol radicals of which contain up to three carbon atoms, for example,mono- di- and triethanolamine; alkylene-diamines which contain up to sixcarbon atoms, such as hexamethylenediamine; phenylalkylamines, forexample, benzylamine, phenylethylamine and N-methylphenylethylamine;cyclic saturated or unsaturated bases containing up to six carbon atoms,such as pyrrolidine, piperidine, morpholine piperazine and their N-alkyland N-hydroxyalkyl derivatives, such as N-methyl-m-orpholine andN-(2-hydroxyethyl)-piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)-morpholinium N,N-dimethylmorpholinium,N-methyl-N-(2-hydroxyethyl)-morphollnium, N,N-dimethylpiperidiniumsalts, which are characterized by having good water-solubility. Inprinciple, however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid of formula 1 in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed ina water-miscible, inert organic solvent, forexample, methanol, ethanol, dioxane, and the like in the presence ofwater. For example, such use of sodium hydroxide, sodium carbonate orsodium bicarbonate gives a solution of the sodium salt. Evaporation ofthe solution or addition of a water-miscible solvent of a more moderatepolarity, for example, a lower alkanol, for instance, butanol, or alower alkanone, for instance, ethyl methyl ketone, gives the solidinorganic salt if that form is desired.

To produce an amine salt, the acidic compound of formula 1 is dissolvedin a suitable solvent of ether moderate or lower polarity, for example,ethanol, methanol, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthan added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of low polarity, for example, benzene or petroleum ether, or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use substantiallyequivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula 1 with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

Also included in this invention are the steroechemical isomers of thecompounds of formula I which result from asymmetric centers, containedtherein. It is to be understood that the diasteromers arising from suchasymmetry are included within the scope of this invention. Suchdiastereomers are obtained in substantially pure form by classicalseparation techniques and by sterically controlled synthesis.

Individual enantiomers, which might be separated by fractionalcrystallization of the diastereomeric salts thereof, are also included.

The compounds of formula 1, or a therapeutically acceptable saltthereof, are useful hypolipidemic agents in a mammal upon oral orparenteral administration. Their hypolipidemic properties are readilydemonstrated by the following method: male albino rats (eight rats pergroup), weighing 140-170g, are given a single daily oral dose of thetest compound by gavage as a suspension in 2% Tween-80* in water(1.0ml). In the same manner, controls are given only 2% Tween-80* in water(1.0 ml) daily. After one week of treatment, animals are decapitated andthe blood is collected. The serum is separated by centrifugation andserum cholesterol levels are measured by the method of A. Zlatkis etal., J. Lab. Clin. Med., 41,486(1953), as modified for the autoanalyzer(Method Np-24). Serum phospholipids are determined by the semi-automatedtechnique of M. Kraml, Clin. Chim, Acta., 13,442(1966) and serumtriglycerides are measured by the semiautomated method of M. Kraml andL. Cosyns, Clin. Biochem., 2,373(1959). The activity of a test compoundis assessed by comparing serum cholesterol, phospholipid and/ortriglyceride levels in rats treated with the test compound and controlrats and the data are analyzed for significance by the Student's t-test.The following results demonstrating hypotriglyceridemic activity arecalculated by subtracting the serum triglyceride level in treated ratsfrom the control serum triglyceride level, and expressing the differenceas a percentage of the control level. The following compounds of formula1 at a dose of 1.0 mmole per kilogram of body weight per day lowertriglyceride levels by the indicated percentage:4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid (42%,described in Example4),4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-5-carboxylic acid(53%, described in Example 4),4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid (37%, described inExample 4), spiro[furan-5(4H), 1' (2'H)-naphthalene]-3',4'-dihydro-4-oxo-2-carboxylic acid (43%, described in Example 4),4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid methyl ester(53%, described in Example 5) and4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid3-pyridinylmethyl ester (61%, described in Example 6).

The compounds of formula 1, or a therapeutically acceptable saltthereof, can be used also in combination with known hypolipidemicagents, for example, clofibrate, for reduction of elevated lipids in amammal. When used in this combination, the compound of formula 1 can beadministered sequentially or simultaneously in combination with aneffective amount of the know hypolipidemic agent. Suitable methods ofadministration, compositions and dosages of clofibrate (ATROMID-S) isdescribed by Charles E. Baker, Jr. "Physician's Desk Reference", MedicalEconomics Company, Oradell, N.J. 1977, pp 593-594, for example, 0.5 to2.0g per patient per day in divided dosages. , The compounds of formula1, or a therapeutically acceptable salt thereof, in combination with aknown hypolipidemic agent, are used in the same manner as describedherein for their use as hypolipidemic agents.

When the compounds of formula 1 of this invention are used ashypolipidemic agents in a mammal, e.g. rats and dogs, they are usedalone or in combination with pharmacologically acceptable carriers, theproportion of which is determined by the solubility and chemical natureof the compound, chosen route of administration and standard biologicalpractice. For example, they are administered orally in solid form, e.g.capsule or tablet. They are also administered orally in the form ofsuspension or solutions, or they may be injected parenterally. Forparenteral administration they may be used in the form of a sterilesolution containing other solutes, for example, enough saline or glucoseto make the solution isotonic.

The tablet compositions for oral administration contain the activeingredient in admixture with non-toxic pharmaceutical excipients knownto be suitable in the manufacture of tablets. Suitable pharmaceuticalexcipients are, for example, starch, milk sugar, certain types of clayand so forth. The tablets can be uncoated or they can be coated by knowntechniques so as to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action.

The aqueous suspensions for oral use of the compounds of the inventioncontain the active ingredient in admixture with one or more non-toxicpharmaceutical excipients, for instance, emulsifying and suspendingagents, known to be suitable in the manufacture of aqueous suspensions.Suitable excipients are, for example, methyl-cellulose, sodium alginate,gum acacia, lecithin and so forth. The aqueous suspension can alsocontain one or more preservatives, one or more colouring agents and/orone or more sweetening agents.

Non-aqueous suspensions for oral use can be formulated by suspending theactive ingredient in a vegetable oil, for example, arachis oil, oliveoil, seasame oil, or coconut oil; or in mineral oil. The suspension cancontain a thickening agent, for example, beeswax, hard paraffin or cetylalcohol. These compositions can also contain a sweetening agent,flavouring agent and antioxidant.

For parenteral administration, which includes intramuscular,intraperitoneal, subcutaneous and intravenous use, the compounds of theinvention can be used in the form of a sterile solution, wherein the pHshould be suitably adjusted and buffered. The solution can contain otherpharmaceutical excipients, for example, enough saline or glucose to makethe solution isotonic.

The dosage of a compound of formula 1 of this invention as ahypolipidemic agent will vary with the form of administration and theparticular host as well as the age and condition of the host undertreatment. Generally, treatment is initiated with small dosagessubstantially less than the optimal dose of the compound. Thereafter,the dosage is increased by small increments until the optimal effectunder the circumstances is reached. In general, a compound of thisinvention is most desirably administered at a concentration that willgenerally afford effective results without causing any harmful ordeleterious side effects. The effective hypolipidemic amount of thecompound usually ranges from about 1.0mg to about 500mg per kilogram ofbody weight per day, although as aforementioned variations will occur.However, a dosage level that is in the range of from about 5 mg to about300 mg per kilogram of body weight per day is employed most desirably inorder to achieve effective results.

Process

For the preparation of the 4,5-dihydro-4-oxofuran-2-carboxylic acidderivatives of formula I, the preferred starting materials are theα-hydroxyketones of formula II ##STR4## in which R¹ and R² each is loweralkyl, cyclo(lower)alkyl, lower alkoxy (lower)alkylene, phenyl or phenylmono- or disubstituted with lower alkyl, lower alkoxy, halo, nitro ortrifluoromethyl; or R¹ and R² together form a --(CH₂)_(m) --X--(CH₂)_(n)-- chain wherein m and n each is an integer from one to four and X ismethylene, oxa or thia; or R¹ and R² together with the carbon atom towhich they are joined form a spiro[1,2,3,4-tetrahydronaphthalene]-I orspiro[indan]-I radical; and R³ is hydrogen or lower alkyl.

The starting materials of formula II in which R¹ and R² are as definedherein and R³ is hydrogen are either known or they can be prepared as isillustrated in reaction scheme I. ##STR5##

With reference to reaction scheme I, a number of acetylenic carbinols offormula IV are known and commercially available. Alternatively,acetylenic carbinols are readily available from addition of a metallicacetylide to the ketone of formula III in which R¹ and R² are as definedherein using the method described by A. W. Johnson, AcetylenicCompounds, Vol. 1, The Acetylenic Alcohols, E. Arnold Co, London, 1946;R. a. Raphael, Acetylenic Compounds in Organic Synthesis, London,Butterworth's Sc. Publ., 1955; P. A. Robins and J. Walker, J. Chem.Soc., 177(1957); and E. D. Bergmann et al., J. Appl. Chem. 3,39(1953).In the preferred method, a mixture of the compound of formula III andlithium or sodium in a solution of anhydrous liquid ammonia saturatedwith gaseous acetylene is allowed to react for nine hours and thecorresponding compound of formula IV is isolated.

The acetylenic carbinols of formula IV are converted to thecorresponding α-hydroxyketones of formula II, by hydration of theacetylenic carbinol in a mixture of mercuric oxide(red form) or mercuricsulfate, aqueous tetrahydrofuran and sulfuric acid at 60°-65° C. for oneto six hours, according to the procedure described by A. W. Johnson,cited above, pp 102-105; E. D. Bergmann and D. F. Herman, J. Appl.Chem., 3,42(1953), G. F. Hennian and B. R. Fleck, J. Amer. Chem. Soc.,77,3253(1955); and G. F. Hennian and E. J. Watson, J. Org. Chem.,23,656(1958).

The starting materials of formula II in which R¹ and R² are as definedherein and R³ is lower alkyl are either known or they can be prepared asis illustrated in reaction scheme 2. ##STR6##

With reference to reaction scheme 2, an organometallic derivative of thecompound of formula VIII is condensed with the ketone of formula III toobtain the corresponding α-hydroxyketone of formula II in which R³ islower alkyl according to the conditions described by I. I. Lapkin and T.N. Povarnitsyna, Zh. Obshch. Khim. 38,99(1968), cf. Chem. Abstr.,69,19233z.

The alternative route starting from the compound of formula V isespecially suitable for preparing the α-keto alcohols of formula II inwhich R¹ or R² is phenyl or phenyl mono- or disubstituted with loweralkyl, lower alkoxy, halo, nitro or trifluoromethyl. Alkylation of thecompound of formula V, using the method of K. Binovic and S. Vrancea,Chem. Ther., 313(1968), gives the corresponding compound of formula VI.The latter compound is brominated, according to the conditions describedby J. R. Catch et al., J. Chem. Soc. 272(1948), to obtain thecorresponding bromo-ketone of formula VII. Conversion of the latterbromoketone to the corresponding α-hydroxyketone of formula II isdescribed by J. G. Aston and R. B. Greenberg, J. Amer. Chem. Soc.,62,2590(1940); J. Kapron and J. Wiemann, Bull. Soc. Chim. France,12,945(1945); and Y. L. Pascal, Ann. Chim. (Paris), 245(1968).

In addition to the above described preparations, α-hydroxyketones offormula II can be prepared by methods described by Y. L. Pascal, citedabove, and P. Kaufmann, J. Amer. Chem. Soc., 26,5794(1954).

Reaction scheme 3 illustrates the conversion of the α-hydroxyketone offormula II to the corresponding compound of formula I in which R¹, R²and R³ are as defined herein. ##STR7##

As illustrated by reaction scheme 3, the compound of formula I in whichR⁴ is hydrogen is prepared from the compound of formula II via the routeII→→ IX→ X→ I. Although the intermediates of formula IX and X can beisolated and further reacted in separate steps, the compound of formulaII can be converted to the corresponding compound of formula I viaintermediates IX and X in a single reaction vessel without isolating thelatter intermedlates.

The first step in the conversion of the α-hydroxyketone of formula II isthe condensation of substantially equimolar amounts of theα-hydroxyketone and a di(lower alkyl)oxalate, preferably dimethyl ordiethyl oxalate, in the presence of one to four molar equivalents of astrong inorganic proton acceptor, preferably sodium hydride, in ananhydrous inert organic solvent. Preferred inert organic solvents can beselected from the di(lower alkyl)ethers or cyclic ethers, for example,diethyl ether, dioxane and tetrahydrofuran. The reaction mixture ismaintained at 30° to 70° C., preferably 50° to 60° C., for 10 to 30hours. The resultant enolate salt is filtered as rapidly as possible,dissolved in water, acidified with a diluted inorganic acid, and thecorresponding compound of formula IX is extracted with an inert waterimmiscible organic solvent, preferably diethyl ether.

Hydrolysis of the latter compound is readily achieved under alkalineconditions with a solution of one to three molar equivalents ofpotassium or sodium hydroxide in an aqueous solution of a water miscibleorganic solvent, preferably methanol, ethanol, tetrahydrofuran ordioxane, at 15° to 30° C. for 15 to 40 hours. The latter solution isextracted with a water immiscible organic solvent, preferably diethylether, benzene, chloroform, dichloromethane and the like, and theextract is evaporated to obtain the corresponding compound of formula X.

The latter compound is cyclized under acidic conditions to obtain thecorresponding compound of formula I in which R¹, R² and R³ are asdefined herein and R⁴ is hydrogen. In one method of achieving thiscyclization, a solution of the compound of formula X and 0.1 to 10 molarequivalents, preferably 0.1 to 0.4 molar equivalents, and an acidcatalyst, for example, hydrogen chloride, hydrogen bromide, hydrochloricacid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid,phosphoric acid, polyphosphoric acid and the like, preferablyp-toluenesulfonic acid or hydrogen chloride, in an inert organicsolvent, preferably benzene or toluene, is maintained at 20° to 100° C.for two to 50 hours. Alternatively, the compound of formula X iscyclized in an aqueous solution containing the acid catalyst at 10° to50° C. for 10 to 50 hours. Preferred acid catalysts for use in theaqueous conditions can be selected from hydrochloric acid, sulfuricacid, hydrobromic acid and phosphoric acid. The aqueous solution usuallyrequires sufficient acid catalyst so that the solution is maintained atpH 0.5 to 3.0 preferably 1.0 to 2.0.

In a modification of the conversion of the compound of formula II to thecorresponding compound of formula I, the above individual steps ofcondensation, alkaline hydrolysis and cyclization are combined in aprocess wherein the intermediates of formula IX and X are not isolated.

In this modification, the α-hydroxyketone of formula II is condensedwith a di(lower alkyl) oxalate in the same manner as described above.However, the reaction mixture is not filtered but instead is mixed withabout an equal volume of water. The resulting aqueous alkaline solutionis, if required, adjusted to pH 10 to 12 with sodium hydroxide andmaintained at pH 10 to 12 and at 15° to 30° C. for 10 or 40 hours andwashed with a water immiscible organic solvent, preferably diethyl etheror benzene. An acid catalyst, preferably hydrochloric acid, hydrobromicacid, sulfuric acid or phosphoric acid, is added to the aqueous solutionuntil the solution reaches pH 0.5 to 3.0, preferably 1.0 to 2.0. Theacidic solution is maintained at 10° to 50° C., preferably 20° to 30°C., for 0.5 to 10 hours and extracted with a water immiscible organicsolvent, for example, ethyl acetate, diethyl ether, benzene, toluenechloroform, dichloromethane and the like. The organic extract isevaporated and, if required, purified to obtain the correspondingcompound of formula I in which R⁴ is hydrogen.

If the aqueous alkaline solution in the latter preparation is maintainedat pH 8 to 9 instead of pH 10 to 12, a corresponding intermediate offormula XI ##STR8## in which R¹, R² and R³ are as defined herein isisolated after acidification of the aqueous alkaline solution. Morespecifically, the α-hydroxyketone of formula II is condensed with adi(lower alkyl) oxalate in the same manner as described above. Thereaction mixture is not filtered but instead is mixed with about anequal volume of water and if necessary the resulting aqueous solution isadjusted to pH 8 to 9 with dilute hydrochloric acid or sodium hydroxide.The resulting aqueous solution is maintained at pH 8 to 9 and at 15° to30° C. for one to five hours and washed with a water immiscible organicsolvent, in the same manner as described above. The mixture isacidified, maintained at 10° to 50° C., preferably 20° to 30° C., forone to 30 minutes and extracted, in the same manner as described abovefor 11→1, to obtain the corresponding intermediate of formula XI.

Reaction of the intermediate of formula XI under aqueous alkalineconditions at pH 10 to 12 gives the corresponding compound of formula Iin which R⁴ is hydrogen. For this reaction, a solution of the compoundof formula II in aqueous potassium or sodium hydroxide is maintained atpH 10 to 12 and at 15° to 30° C. for 10 to 40 hours and washed with awater immiscible organic solvent, in the same manner as described above.Subsequently, acidification of the aqueous solution, maintenance of theacidic solution and extraction, in the same manner as described abovefor 11→1, gives the corresponding compound of formula I in which R⁴ ishydrogen.

The acidic compound of formula I in which R⁴ is hydrogen is esterifiedto obtain the corresponding ester of formula I in which R⁴ is loweralkyl, cyclo(lower)alkyl, phenyl(lower)alkylene, amino(lower)alkylene,lower alkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene. A number of esterification methods can beused, for example, mixed anhydride; dehydrative coupling reagents, forinstance, dicyclohexylcarbodiimide; acid catalysts; diazoalkanes; andacid chloride.

A preferred method of esterification employs an acid catalyst,preferably 0.1 to 1.0 molar equivalents of anhydrous sulfuric acid orhydrogen chloride, and 2 to 50 equivalents of a lower alkanol,hydroxycyclo(lower)alkane, phenyl(lower)alkanol, amino(lower)alkanol,lower alkylamino(lower)alkanol, di(lower alkyl)amino(lower)alkanol or3-pyridinyl(lower)alkanol at 50° to 100° C. for one to ten hours. Itshould be noted that when amino(lower)alkanol, loweralkylamino(lower)alkanol, di(lower alkyl)amino(lower)alkanol or3-pyridinyl(lower)alkanol is used, then a corresponding additional molarmount of the acid catalyst should be present in the reaction vessel. Ifthe reactants are mutually soluble, a solvent for the esterification canbe omitted. Otherwise, any anhydrous inert organic solvent can be used,for example, dimethylformamide, benzene, toluene, chloroform and thelike.

Another preferred method of esterification proceeds through the acidchloride. In this method, a solution of the acidic compound of formula Iin which R⁴ is hydrogen and 5 to 50 molar equivalents of thionylchloride is heated at 50° to 80° C. for one to ten hours and evaporatedto obtain the corresponding acid chloride. A solution of the latter acidchloride, one to ten molar equivalents of the above noted alcohols andan organic proton acceptor, for example, pyridine or triethylamine, inan inert organic solvent, for example, acetone, benzene,dichloromethane, toluene, chloroform or dimethylformamide, preferablyacetone, is maintained at 0° to 50° C. for to two to ten hours.Evaporation and purification affords the compound of formula I in whichR¹, R² and R³ are as defined herein and R⁴ is lower alkyl,cyclo(lower)alkyl, phenyl(lower)alkylene, amino(lower)alkylene, loweralkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene.

The following examples illustrate further this invention.

EXAMPLE 1 3-Hydroxy-4-methyl-3-phenyl-1-pentyne (IV:R.sup. 2 = CH(CH₃)₁and R² = Ph)

A reaction flask, equipped with a dry-ice reflux condenser, is chargedwith 700 ml of freshly condensed liquid ammonia. The ammonia gas ispassed through a tower of potassium hydroxide pellets. Upon stirring, arapid stream of acetylene gas (dried in a sulfuric acid wash bottle) isintroduced into the ammonia for 10 min, then the rate of passage of theacetylene is reduced and a continuous flow of acetylene through thereaction mixture is maintained during the following operations (approx.9 hr). Small pieces of sodium (9.2 g) are inserted, and 2 hr later,2-methyl-1-phenyl-1-propanone (50 g) is added dropwise. The stirring iscontinued for 6 hr at -33° C. then, the stream of acetylene is shut off,and the ammonia is allowed to evaporate in the hood (overnight). Afteradding cautiously ice-water, the resultant solution is acidified withdiluted sulfuric acid, and extracted with diethyl ether. The combinedextracts are washed with saturated brine, dried over magnesium sulfate,filtered, and evaporated to yield 45.5 g of the title compound, ir(CHCl.sub. 3) 3600, 3310, 1450, and 1010 cm⁻¹ and nmr (CDCl₃) δ 0.85 and1.07 (d), 2.10(heptuplet), 2.35(s), 2.66(s), 7.27(m) and 7.55(m).

EXAMPLE 2 3-Hydroxy-4-methyl-3-phenyl-2-pentanone (II:R.sup. 2 =CH(CH₃)₂, R¹ = Ph and R³ = H)

To a refluxing mixture of tetrahydrofuran (70 ml), water (5 ml), andconc. sulfuric acid (1.5 g) is added 1 g of red mercuric oxide and thereflux is continued for 5 min. Then, the inside temperature is adjustedto 60°-62° C. and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentyne(described in Example 1) is added. The reaction is exothermic(spontaneous mild reflux) and there is a noticeable clearing of themixture. Another 1 g of mercuric oxide is added, and the solution isrefluxed for 30 min. The reaction mixture is stirred at 60° C. for anadditional 3 hr, during which time the precipitation of a mercury sludgeoccurred. After cooling, the slurry is diluted with 100 ml of diethylether and filtered through diatomaceous earth. The filter cake is washedwith 200 ml of diethyl ether, and the combined filtrates are washedrepeatedly with water, dried over magnesium sulfate, filtered, andevaporated to give 10.6 g of the title product, ir (CDCl₃) 3470 and1715-1710 cm⁻¹ and nmr (CDCl₃) δ 0.91(d), 2.15(s), 2.79(heptuplet),4.39(s) and 7.20-7.65(m).

EXAMPLE 3 3-Hydroxy-3-phenyl-2-butanone(II: R² = Me, R¹ = Ph and R³ =H).

The title compound is prepared by using a modified method of G. F.Hennion and B. R. Fleck, J. Amer. Chem. Soc., 77,3258(1955). To amixture of methanol (5 ml), water (0.2 ml), sulfuric acid (100 mg), andmercuric sulfate (100 mg) is added at 55° C. a solution of3-hydroxy-3-phenyl-1-butyne (2 g) in 90% aqueous methanol (5 ml) over aperiod of 90 min. The reaction is slightly exothermic, and the insidetemperature is maintained at 55°-57° C. During the reaction time, 50 mgof mercuric sulfate is added. When addition of the acetylenic componentis complete, another portion (50 mg) of mercuric sulfate is added, andthe mixture is stirred at 55° C. for 1 hour. During this time 1 ml ofwater is added. After cooling, the reaction mixture is poured intoice-water and extracted with diethyl ether. The combined extracts arewashed with water, dried over magnesium sulfate, filtered andevaporated. The resultant oil is chromatographed on silica gel usingbenzene. The appropriate eluates are evaporated to give 0.5g of thetitle compound, ir(CHCl₃)3450 and 1741 cm⁻¹ and nmr(CDCl₃) δ 1.75(s),2.08(s), 4.50(s) and 7.40(m).

In the same manner but replacing 3-phenyl-3-hydroxy-1-butyne with anequivalent amount of 3-hydroxy-3-(4-chlorophenyl)-1-butyne,3-hydroxy-3-methyl-1-butyne, 1-ethynyl-1,2,3,4-tetrahydronaphthalene,3-ethyl-3-hydroxy-1-heptyne, 3-hydroxy-3, 3-diphenyl-1-propyne,3-cyclohexyl-3-hydroxy-1-hexyne, 4-ethoxy-3-(3-methoxyphenyl)-3-hydroxy-1-butyne,3-(3,4-diethylphenyl)-3-hydroxy-3-(4-nitrophenyl)-1-propyne,3-ethynyl-3-hydroxytetrahydrofuran, 1-ethynyl-1-hydroxycyclohexane,1-ethynyl-1-hydroxyindane or 3-cyclopentyl-5-ethoxy-3-hydroxy-1-pentyne,the following compounds of formula II are obtained, respectively:3-hydroxy-3-(4-chlorophenyl)-2-butanone, ir (CHCl₃)3440 and 1710 cm⁻¹,3-hydroxy-3-methyl-2-butanone,1-acetyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene ir(film) 3450 and 1710cm⁻¹, 3-ethyl-3-hydroxy-2-heptanone, 3-hydroxy-3,3-diphenyl-2-propanone,3-cyclohexyl-3-hydroxy-2-hexanone,4-ethoxy-3-(3-methoxyphenyl)-3-hydroxy- 2-butanone,3-(3,4-diethylphenyl)-3-hydroxy-3-(4-nitrophenyl)-2-propanone,3-acetyl-3-hydroxytetrahydrofuran, 1-acetyl-1-hydroxycyclohexane,1-acetyl-1-hydroxyindane and3-cyclopentyl-5-ethoxy-3-hydroxy-2-pentanone.

EXAMPLE 4 4,5-Dihydro-5-methyl-4-oxo-5phenylfuran-2-carboxylic acid(I:R² = Me, R¹ = Ph, and R³ and R⁴ = H)

To a stirred suspension of sodium hydride (10.5 g, 54% in mineral oil)in dry tetrahydrofuran (400 ml) is added dropwise a solution of diethyloxalate (16 g) and 3-hydroxy-3-phenyl-2-butanone (16.4 g described inExample 3) in tetrahydrofuran (50 ml). The solution temperature ismaintained at 55°-60° C., and the solution is maintained at thistemperature for 18 hr after the addition is complete. The cold reactionmixture is poured into water, the mixture is adjusted to pH 11 withsodium hydroxide and allowed to stand for 24 hours, and washed withdiethyl ether. Upon addition of 6N hydrochloric acid, the aqueoussolution is adjusted to pH 1. The acidic mixture is kept at 20° to 30°C. for 2 hours and extracted with diethyl ether. The ether extract isdried and slowly evaporated to obtain crystals (20 g) of the titlecompound, mp 174°-176° C.

ANAL: Calculated for C₁₂ H₁₀ O₄ : C, 66.06; H, 4.62%: Found: C, 66,41;H,4.69%.

A solution of the title compound in diethyl ether and a solution of anequimolar amount of benzylamine in diethyl ether are mixed at 0° C. Theprecipitate is collected by filtration and crystallized from isopropanolto obtain the benzylamine salt of the title compound mp 192°-193° C.

In the same manner but replacing 3-hydroxy-3-phenyl-2-butanone with anequivalent amount of another compound of formula II described in Example2 and 3, the following compounds of formula I are obtained,respectively:4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acid, mp151°-153° C. and nmr (CDCl₃) δ0.77(d), 1.01(d), 2.85(heptuplet) 6.03(s),6.45(s) and 7.33(m);5-(4-chlorophenyl)-4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid, mp169° C. and nmr (CDCl₃) δ1.75(s), 6.25(s) and 7.45(m);4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid, mp 180°-181° C.and ir (nujol) 2800(broad), 1737, 1670 and 1600 cm⁻¹ ;spiro[furan-5(4H), 1'(2'H)-naphthalene]-3',4'-dihydro-4-oxo-2-carboxylicacid, mp 152°-154° C. and nmr (MeOH-d₄) δ2.07(m), 2.84(t), 6.29(s) and6.8-7.4(m); 5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid;4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid;5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid;4,5-dihydro-5-ethoxymethyl-5-(3-methoxyphenyl)-4-oxofuran-2-carboxylicacid;4,5-dihydro-5-(3,4-diethylphenyl)-5-(4-nitrophenyl)-4-oxofuran-2-carboxylicacid; 1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid;1-oxaspiro[4,5]dec-2-ene-4-oxo-2-carboxylic acid; spirop[furan-5(4H),1'-indan]-4-oxo-2-carboxylic acid; and5-cyclopentyl-4,5-dihydro-5-(3-ethoxypropyl)-4-oxofuran-2-carboxylicacid.

EXAMPLE 5 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic AcidMethyl Ester (I: R² and R⁴ =Me, R¹ =Ph and R³ =H)

A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid(0.4 g, described in Example 4), absolute methanol (50 ml), and sulfuricacid (3 drops) is refluxed overnight and evaporated. The residue isdiluted with 50 ml of diethyl ether, and the solution is washed quicklywith saturated sodium bicarbonate and water, dried over magnesiumsulfate, filtered, and evaporated. The residue is crystallized fromdiethyl ether to obtain the title compound (0.32 g) mp 60°-62° C. andnmr (CDCl₃) δ1.81(s), 3.99(s), 6.25(s) and 7.42(m).

In the same manner but replacing methanol with an equivalent amount ofethanol, propanol or butanol, the following compounds of formula I areobtained, respectively:4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid ethyl ester,4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid propyl esterand 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid butylester.

Similarly, but replacing4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid with anequivalent amount of another compound of formula I described in Example4, the following compounds of formula I are obtained, respectively:4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acidmethyl ester;5-(4-chlorophenyl)-4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acidmethyl ester; 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acidmethyl ester, mp 66° C., ir(CHCl₃)1720, 1695 and 1575 cm⁻¹ ;spiro[furan-5(4H), 1'(2'H)-naphthalene]-3',4'-dihydro-4-oxo-2-carboxylicacid methyl ester; 5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylicacid methyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acidmethyl ester; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylicacid methyl ester;4,5-dihydro-5-ethoxymethyl-5-(3-methoxyphenyl)-4-oxofuran-2-carboxylicacid methyl ester;4,5-dihydro-5-(3,4-diethylphenyl)-5-(4-nitrophenyl)-4-oxofuran-2-carboxylic acid methyl ester;1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid methyl ester;1-oxaspiro[4,5]dec-2-ene4-oxo-2-carboxylic acid methyl ester;spiro[furan-5-(4H),1'-indan]-4-oxo-2-carboxylic acid methyl ester; and5-cyclopentyl-4,5-dihydro-5-(3-ethoxypropyl)-4-oxofuran-2-carboxylicacid methyl ester.

EXAMPLE 6 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic Acid3Pyridinylmethyl Ester (I: R² =Me, R¹ =Ph, R³ =H and R⁴=3-pyridinylmethyl).

A mixture of 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid(8.75 g, described in Example 4) and thionyl chloride (90 ml) isrefluxed for 3 hr and evaporated. The residue is dissolved in benzene(100 ml) and evaporated (twice). The infrared spectrum of the residue isindicative of a quantitative conversion of the carboxylic acid into thecarbonyl chloride, ir (CHCl₃) 1820 and 1795, 1755 and 1715 cm⁻¹. Thismaterial is dissolved in 50 ml of dry acetone and added to a mixture of3-pyridinemethanol (4.8 g), pyridine (3.1 g), and acetone (100 ml) at 0°C. The reaction mixture is stirred at 20° to 30° C. temperature for 4 hrand evaporated under reduced pressure. The residue is partitionedbetween chloroform and saturated sodium bicarbonate. The organic phaseis collected, dried and evaporated to give 8.8 g of the title compound,ir (CHCl₃) 1753, 1742, 1715 (broad), 1595 and 1100 cm⁻¹ and nmr (CDCl₃)δ1.78(s), 5.45(s), 6.29(s), 7.42(m), 7.84(doublet of triplets) and8.60(m).

The title compound (18 g) is dissolved in acetone (20 ml) and a solutionof hydrogen chloride in diethyl ether is added until precipitation iscomplete. The solvent is decanted and the residue is triturated withdiethyl ether. The residue is crystallized from acetone to obtain thehydrochloride salt (15 g) of the title compound, mp 124°-125° C.

ANAL: Calculated for C₁₈ H₁₅ NO₄.HCl: C,62.52; H,4.66; N,4.05%; Found:C,62.30; H,4.53; N,3.94%.

A solution of the title compound in diethyl ether and a solution of ahalf molar equivalent of (E)-2-butenedioic acid in isopropanol arecombined at -10° C. The resulting precipitate is filtered andcrystallized from acetonitrile to obtain the hemi-(E)-2-butenedioatesalt, mp 128°-130° C., of the title compound.

In the same manner but replacing4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid with anequivalent amount of another compound of formula I described in Example4, the following compounds of formula I are obtained, respectively:

4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acid3-pyridinylmethyl ester;5-(4-chlorophenyl)-4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid3-pyridinylmethyl ester, nmr(CDCl₃)δ1.77(s), 5.46(s), 6.29(s), 7.42(m),7.86(m) and 8.70(m); 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylicacid 3-pyridinylmethyl ester, mp 109°-110° C.;spiro[furan-5(4H),-1'(2'H)-naphthalene]-3',4'-dihydro-4-oxo-2-carboxylicacid 3-pyridinylmethyl ester;5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid3-pyridinylmethyl ester;4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid 3-pyridinylmethylester; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid3-pyridinylmethyl ester;4,5-dihydro-5-ethoxymethyl-5-(3-methoxyphenyl)-4-oxofuran-2-carboxylicacid 3-pyridinylmethyl ester;4,5-dihydro-5-(3,4-diethylphenyl)-5-(4-nitrophenyl)-4-oxofuran-2-carboxylicacid 3-pyridinylmethyl ester; 1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid 3-pyridinylmethyl ester;1-oxaspiro[4,5]dec-2-ene-4-oxo-2-carboxylic acid 3-pyridinylmethylester; spiro[furan-5(4H), 1'-indan]-4-oxo-2-carboxylic acid3-pyridinylmethyl ester; and5-cyclopentyl-4,5-dihydro-5-(3-ethoxypropyl)-4-oxofuran-2-carboxylicacid 3-pyridinylmethyl ester.

EXAMPLE 7 6-Methyl-6-phenyltetrahydropyran-2,3,5-trione (XI: R² =Me, R¹=Ph and R³ =H)

To a stirred suspension of sodium hydride (10.5 g 54% in mineral oil) indry tetrahydrofuran (400 ml) is added dropwise a solution of diethyloxalate (16 g) and 3-hydroxy-3-hydroxy-3-phenyl-2-butanone (16.4 gdescribed in Example 3) in tetrahydrofuran (50 ml). The solutiontemperature is maintained at 55°-60° C., and the solution is maintainedat this temperature for 18 hr after the addition is completed. The coldreaction mixture is poured into water and the mixture is adjusted pH 8to 9 with sodium hydroxide or hydrochloric acid. This mixture at pH 8 to9 is allowed to stand for 24 hr and extracted with diethyl ether. Theether extract is dried, evaporated and crystallized from diethyl etherto obtain the title compound: mp 142°-144° C.; ir (nujol) 3130, 1718 and1640 cm⁻¹ ; uv (MeOH) λ_(max) 268 nm (ε=8830) and nmr (MeOH-d₃ ) δ1.89(s), 5.92 (s) and 7.34 (s).

Anal. Calc'd for C₁₂ H₉ O₄ : C, 66.05; H, 4.62% Found: C, 66.14; H,4.83%.

EXAMPLE 8 4,5-Dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid(1:R² =Me, R¹ =Ph, and R³ and R⁴ =H)

A mixture of 6-methyl-6-phenyltetrahydropyran-2,3,5-trione (2.18 g,described in Example 7) in aqueous sodium hydroxide (15 ml) at pH 11 isstirred for 24 hr and washed with diethyl ether. Hydrochloric acid (6N)is added until the solution becomes acidic at pH 1 to 4. The precipitateis collected and crystallized from diethyl ether to obtain the titlecompound (2.0 g), mp 174°-176° C.

We claim:
 1. A process for preparing a compound of formula 1 ##STR9## inwhich R¹ and R² each is lower alkyl, cyclo(lower)alkyl, loweralkoxy(lower)alkylene, phenyl or phenyl mono- or disubstituted withlower alkyl, lower alkoxy, halo, nitro or trifluoromethyl; or R¹ and R²together form a --(CH₂)_(m) --X--(CH₂)_(n) -- chain wherein m and n eachis an integer from one to four and X is methylene, oxa or thia; or R¹and R² together with the carbon atom to which they are joined form aspiro[1,2,3,4-tetrahydronaphthalene]-1 or spiro-[indan]-1 radical; R³ ishydrogen or lower alkyl; and R⁴ is hydrogen, lower alkyl,cyclo(lower)alkyl, phenyl(lower)alkylene, amino(lower)alkylene, loweralkylamino(lower)alkylene, di(lower)alkylamino(lower)alkylene or3-pyridinyl(lower)alkylene, which comprises: reacting a compound offormula 11 ##STR10## in which R¹, R² and R³ are as defined herein with adi(lower alkyl) oxalate in the presence of a strong inorganic protonacceptor under anhydrous conditions, hydrolyzing the mixture with waterat about pH 10 to about pH 12, and allowing the latter mixture to standunder acidic conditions to obtain the compound of formula 1 in which R¹,R² and R³ are as defined herein and R⁴ is hydrogen; and ifdesired,esterifying the latter compound of formula 1 to obtain thecorresponding compound of formula 1 in which R¹, R² and R³ are asdefined herein and R⁴ is lower alkyl, cyclo(lower)alkyl,phenyl(lower)alkylene, amino(lower)alkylene, loweralkylamino(lower)alkylene, di(lower alkyl)amino(lower)alkylene or3-pyridinyl(lower)alkylene.
 2. A process according to claim 1, whereinR¹ is lower alkyl, phenyl or phenyl monosubstituted with halo; R² islower alkyl; or R¹ and R² together with the carbon atom to which theyare joined form a spiro[1,2,3,4-tetrahydronaphthalene]-1 radical; R³ ishydrogen and R⁴ is hydrogen, lower alkyl or 3-pyridinyl(lower)alkylene.3. A process, as claimed in claim 1, wherein acidic conditions isobtained by the addition of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid or polyphosphoric acid.
 4. A process, asclaimed in claim 1, wherein said strong inorganic proton acceptor issodium hydride.
 5. A process, as claimed in claim 1, wherein saiddi(lower alkyl) oxalate is selected from dimethyl oxalate or diethyloxalate.
 6. The process of claim 1 for the synthesis of atherapeutically acceptable addition salt of said compound of formula 1in which R¹, R² and R³ are as defined therein and R⁴ is hydrogen,amino(lower)alkylene, lower alkylamino(lower)alkylene, di(loweralkyl)amino(lower)alkylene or 3-pyridinyl(lower)alkylene, wherein saidcompound of formula 1 in which R¹, R² and R³ are as defined herein andR⁴ is hydrogen is reacted with a therapeutically acceptable organic orinorganic base to obtain the corresponding thereapeutically acceptableorganic or inorganic base addition salt of said compound of formula 1 inwhich R¹, R² and R³ are as defined herein and R⁴ is hydrogen; or saidcompound of formula 1 in which R¹, R² and R³ are as defined herein andR⁴ is amino(lower)alkylene, lower alkylamino(lower)alkylene, di(loweralkyl)amino(lower)alkylene or 3-pyridinyl(lower)alkylene is reacted witha therapeutically acceptable acid to obtain the correspondingtherapeutically acceptable acid addition salt of said compound offormula 1 in which R¹, R² and R³ are as defined herein and R⁴ isamino(lower)alkylene, lower alkylamino(lower)alkylene, di(loweralkyl)amino(lower)alkylene or 3-pyridinyl(lower)alkylene.